Electrical interventions in medicine are widespread and growing, but basic interaction mechanisms are often poorly understood. Electroporation is an major example. Conventional electroporation is widely used in biomedical research with empirically adjusted delivery of DNA, proteins, cancer drugs and fluorescent markers into cells. Recently discovered supra-electroporation has limited drug delivery capability, but causes intracellular effects by interactions with organelles. Supra-electroporation also removes cells by triggering apoptosis whereas excessive conventional electroporation leads to necrosis. The great majority of research applications are in vitro, but there is rapidly growing empirical investigation of electroporation in vivo. We propose continued basic investigation of the interaction of electric fields with cells and tissue by using advanced modeling. Although we will consider localized heating and other mechanisms (e.g. voltage-gated channels) we will focus on the fundamental mechanisms for the highly non-linear behavior of electroporation. Throughout our investigation we will create and extend mechanistic hypotheses by creating corresponding, realistic cell- and tissue-level models that can account for the: (1) electrical response to simple and complex applied waveforms, (2) amount of Thicroscopic (cell level) heating, and (3) field-induced transport of particular ions and molecules. Our methods involve coupled electrical, thermal and chemical system models. Each system model consists of a large number of interconnected local models that interact to define a system response. These methods allow us to create cell models with realistic, irregular shapes for the outer plasma membrane and also for internal organelle membranes. Our cell-level models can be integrated with tissue-level models for electrical, thermal and chemical responses. Chemical response models can be further expanded to involve pharmacokinetic models. This integrates cell- and tissue-level models to describe chemical changes at the whole body level. We will test our mechanistic-based models by direct comparison of modeling results with published results and experimental findings of our collaborators. This mechanism-based modeling capability will assist engineering of bioelectric interventions by providing preliminary assessment of cellular responses for different pulsing waveforms in a large parameter space. The proposed research is relevant to public health because quantitative mechanistic understanding is critical to developing effective bioelectric medical devices and interventions while minimizing side effects.